A primary challenge in pancreatic cancer is preventing tumor recurrence in patients following a ?curative intent? resection procedure (5-year survival rate 21%). It is believed that, in a subset of patients, the primary cause of tumor recurrence is small sub-cm and sub-mm disease that is unseen and, therefore, un-resected at the time of surgery. To address this problem, researchers are developing new Fluorescently-Guided Cytoreductive Surgery (FGCS) techniques with the goal of enabling surgeons to intraoperatively detect and resect sub-cm and sub-mm tumors. These techniques administer a fluorescent probe?such as a fluorescently-conjugated antibody, small molecule, peptide, quantum dot or nanoparticle?that localizes to tumors thereby facilitating identification of tumor tissue. Localization to the tumor is generally achieved via one of two broadly classified targeting strategies: ?Passive Targeting? via the enhanced-permeability and retention (EPR) effect; or, ?Active Targeting? through the incorporation of a targeting moiety or antibody into the probe. However, none of these technologies is able to identify sub-cm and sub-mm disease. This proposal develops a novel, patented, fluorescent probe, the ?highly- fluorescent rhodamine-labeled expansile nanoparticle? (HFR-eNP), that targets tumors via a unique Materials- Based Targeting strategy. This mechanism leverages both the material functionality of the nanoparticle polymer (e.g., swelling) and fundamental pathophysiological properties of tumors (e.g., increased metabolic rate) to achieve tumor-specific localization with >95% accuracy. We hypothesize that by using HFR-eNPs to guide cytoreductive surgery of disseminated sub-cm and sub-mm tumors, we will significantly improve overall survival compared to unguided resections. Preliminary data demonstrate: 1) HFR-eNPs possess 5- to 10-fold increased fluorescence compared to equivalent concentrations of free rhodamine and can be sterilized with gamma irradiation without significant loss of this fluorescence; 2) large-scale production of HFR-eNPs on a clinical (i.e., 1 liter batch) scale; 3) non-toxicity of the HFR-eNPs in vitro and in vivo; 4) sensitive and specific localization to sub-cm and sub-mm pancreatic tumors in vivo; and, 5) proof-of-concept HFR-eNP-guided cytoreductive surgery to remove large (>1 cm), sub-cm and sub-mm tumors in vivo. Two key Go/No-Go decisions regarding the com- mercialization of this technology are addressed in this proposal. First, in order to be used clinically, a sterilization protocol must be developed that does not alter the HFR-eNP polymer or quench the rhodamine fluorescence. And, following sterilization, the in vivo functionality/tumor localization of the particles must be confirmed. Second, the benefit afforded by using HFR-eNPs to guide the resection of pancreatic tumors, in particular sub-cm and sub-mm tumors, must be quantified through an in vivo cytoreductive surgery model. Thus, the aims of this proposal are:
Aim 1) Sterilize HFR-eNPs via Gamma irradiation and confirm tumor localization post-sterilization;
Aim 2) Determine the improvement to survival afforded by HFR-eNP-guided surgical resections.
A subset of pancreatic cancer patients are candidates to receive ?complete? tumor resections (i.e., removal of all tumor, which is expected to be curative); however, most of these patients suffer from high rates of tumor recurrence?a problem that likely occurs because of small sub-centimeter and sub-millimeter tumors that are unseen, and therefore un-removed, at the time of surgery. This SBIR Phase I proposal furthers the development of a highly-fluorescent nanoparticle technology that employs a novel Materials-Based Targeting strategy to localize specifically to sub-cm and sub-mm tumors. These nanoparticles, whose fluorescence can be seen with the naked eye (this is in contrast to most fluorescent surgical guides which require complicated and expensive cameras and imaging equipment to see) may provide an inexpensive, easy-to-use technology that will enable surgeons to obtain more complete removal of pancreatic tumors and, thereby, to improve patient outcomes and survival.
|Herrera, Victoria Lm; Colby, Aaron H; Ruiz-Opazo, Nelson et al. (2018) Nucleic acid nanomedicines in Phase II/III clinical trials: translation of nucleic acid therapies for reprogramming cells. Nanomedicine (Lond) 13:2083-2098|